The Skinny on Body Fat and HIV

By Nelson Vergel

From ACRIA and GMHC

Summer 2009

Some people with HIV complain of weight and belly fat gain after they start HIV treatment. But researchers have not been able to determine what causes the problem. Some studies actually dispute that there is a problem, and say that people with HIV do not have more visceral fat than HIV-negative people. But the HIV community as a whole has come to accept the fact that body changes happen to some people living with this virus. The problems associated with increased visceral fat include poor body image, depression, bloating, fatigue, sleep apnea (breathing problems), and possible heart problems. It not only affects the way people look -- it could lower their chances of long-term survival.

Fortunately, the HIV meds most often linked to these problems are no longer commonly used, and newer meds are less likely to lead to changes in body shape and fat metabolism. Data from the several studies, including the Swiss HIV Cohort Study, showed that the use of drugs like Zerit and Retrovir (AZT) declined sharply from 2000 to 2006, along with the number of people who experience body changes.

Lipodystrophy (abnormal fat distribution) has been reported in many HIV studies. It includes one or more of the following: lipoatrophy -- a decrease in the subcutaneous fat directly under the skin (associated mostly with the use of Zerit or AZT); lipohypertrophy -- an increase in the visceral fat deep in the belly; increases in bad (LDL) cholesterol and triglycerides; and decreases in good (HDL) cholesterol, sometimes with an increase in blood sugar. The majority of people taking HIV meds do not experience any body shape changes, but some experience one or more of these metabolic complications. A 2007 meta-analysis of several studies estimated that between 14% and 40% of people taking HIV meds have some form of lipodystrophy.

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The Multicenter AIDS Cohort Study (MACS) recently reported that men with HIV in general weigh less than HIV-negative men, but their visceral fat is about the same. Most men with HIV were thinner due to subcutaneous fat loss in the arms, legs, and buttocks, but had as much internal belly fat as the heavier HIV-negative men.

Fortunately, there have been advances in our understanding of lipoatrophy. We now know that it is often linked to the use of Zerit or AZT, and there are two FDA-approved treatments for facial lipoatrophy: Sculptra and Radiesse. However, the same cannot be said about lipohypertrophy, which seems to be caused by many factors. Researchers have not been able to blame any specific drugs. Several studies report that people starting standard HIV combinations have an average increase in visceral fat of 15% after 96 weeks.

An analysis of people in the French APROCO study found that those who started HIV meds with lower CD4 counts gained more visceral fat, possibly due to the large change in their CD4 counts.

It was first thought that protease inhibitors were the main culprits of belly fat gain, but several studies that did not include protease inhibitors also showed increases in visceral fat. An analysis of people in the French APROCO study found that those who started HIV meds with lower CD4 counts gained more visceral fat, possibly due to the large change in their CD4 counts. An analysis of a study comparing Aptivus to Kaletra showed that when taken with Viread and Epivir, the drugs did not increase visceral fat in those who start them with a CD4 count above 250. Some other studies have shown that people who start a protease inhibitor or non-nucleoside along with Zerit, AZT, or Videx seem to have more visceral fat gain than those who start them with other nucleosides. So, the bad guys linked to lipoatrophy may also worsen belly fat.

Switching from a protease inhibitor to Sustiva or Viramune while taking Zerit or AZT has not helped in lowering visceral fat. But a recent small study showed that people who switched from Kaletra to Reyataz while taking Truvada had a decrease of 15% in visceral fat after 6 months. So, we may start to see differences in how HIV meds affect the body when taken with newer nucleoside analogs like Truvada.

Insulin resistance is linked to fat gain, regardless of HIV status. Insulin is a hormone produced by the pancreas, and controls blood glucose (sugar). It captures glucose and pushes it into muscle tissue where it is stored as glycogen for later use as energy. Protease inhibitors may interfere with that process. Also, some people may have a genetic predisposition to insulin resistance. Zerit, AZT, Crixivan, higher doses of Norvir, and most protease inhibitors have been shown in lab studies to impair the action of insulin. This may be a part of the puzzle, but not the entire explanation for visceral fat gain. Aging, poor diet and a lack of exercise may make someone more prone to lipohypertrophy, but people who follow a healthy diet and an exercise program may still suffer from this problem.

What To Do?

Several treatments and approaches have been and are being studied:

Human growth hormone can lower belly fat, but not without side effects. Serostim (a brand of HGH) is approved to treat HIV wasting, but its side effects led the FDA to deny its approval for lipodystrophy. These included joint pain, edema (water retention), increased lipoatrophy and blood sugar increases. Its high cost and lack of insurance reimbursement (due to its lack of FDA approval) are also barriers to use. It requires daily or every other day injections under the skin. But it has been shown to decrease visceral fat by 30% in 6 months.

Tesamorelin is a copy of a hormone that causes the pituitary gland to produce growth hormone. It will soon be up for FDA approval, but, as with Serostim, the FDA may deny approval if no health benefits are seen. Like Serostim, it requires daily injections under the skin but it seems to have milder side effects: mild edema, some joint pain, and a hypersensitivity reaction in 10% of people (sweating and rash). But it does not increase blood sugar or cause lipoatrophy, and it may lower triglycerides, a problem caused by some HIV meds. It has been shown to decrease visceral fat by 15% in 6 months.

Activists are concerned that its price will be high. This could cause insurance companies and Medicare to deny payment since it may be perceived as a cosmetic product. Also, it will be sold in the U.S. by Serono, the same company that sells Serostim. Serono has had poor relations with activists in the past, and was also fined over $700 million by Medicare for using fraudulent practices to induce some physicians to prescribe Serostim.

Leptin is another new contender in the search to decrease visceral fat. This hormone, discovered in 1994, is produced by fat cells. Leptin levels in the blood are generally proportional to the level of body fat. In the hypothalamus (the part of the brain that controls appetite), high levels of leptin suppress the appetite and stimulate fat-burning. Like Serostim, it is taken as an injection under the skin, but it requires two injections a day, though other doses may be studied in the future. In a study of eight men with HIV and lipodystrophy, visceral fat decreased by 32% after 6 months, with no change in subcutaneous fat. Bad (LDL) cholesterol decreased by 16% and good (HDL) cholesterol increased by 19%, with a significant decrease of triglycerides. Leptin was well tolerated but it decreased lean mass. Early, small studies have not shown leptin to have negative effects on blood sugar, as Serostim can. But activists are asking its manufacturer to do larger studies in people with HIV to determine if leptin is useful and if it will be cost-effective.

Metformin is a diabetes drug that at first showed promise in reducing abdominal fat. But later studies have not confirmed this, and have in fact shown that it may worsen lipoatrophy. However, in people without lipoatrophy who have glucose intolerance, metformin may reduce the risk of diabetes and therefore, abdominal fat. Its effects may be enhanced by exercise. Metformin improves insulin sensitivity, triglycerides, and fatty liver, but can cause diarrhea and weight loss (which may itself lead to a decrease in visceral fat). Some people have reported low blood sugar and dizzy spells, so users of this drug should have snacks at hand to increase blood sugar if needed.

Testosterone gels (Androgel, Testim) can reduce waist size in men, but only by lowering subcutaneous fat. In studies, no visceral fat decreases were seen. Testosterone is usually prescribed for people with HIV who have low blood levels of natural testosterone. Data in women are lacking, but one study of 23 women found that those with HIV-related lipodystrophy had higher testosterone levels than HIV-positive women without lipodystrophy. Gels, injections, and a new subcutaneous pellet delivery system are becoming more commonly accepted by physicians.

Oxandrin, an oral anabolic steroid, showed encouraging results for decreasing visceral fat in a small pilot study. But LDL cholesterol increased and HDL cholesterol decreased, along with a small decrease in subcutaneous fat. No body fat studies have been done with the other commonly used anabolic steroid, nandrolone decanoate.

Nutrition studies are lacking. A study at Tufts showed a trend toward less lipodystrophy in those who exercised and increased their soluble fiber (fruits and vegetables). More research is needed on low-carbohydrate diets, which have been shown to improve insulin resistance and visceral fat in HIV-negative people. One observational cohort found that people with HIV eat more saturated fats, which could lead to fat problems. A study of nutrition and lifestyle modifications resulted in decreased belly fat in people with HIV, so there is a clear need for more care providers and organizations to include nutrition and exercise information in their educational efforts.

Sticking to an exercise program can be a challenge for many people who lead busy lives or can't afford to join a gym. But effective home exercise programs are available and could be part of the health counseling given by health care providers and organizations.

Aerobic exercise and weight training decreased triglycerides and visceral fat in a small pilot study. Another study showed that strength training increased lean body mass and decreased fat mass more than aerobic exercise, while improving cholesterol and triglycerides. A regimen of an hour of strength training combined with 20 minutes of aerobic exercise three to four times a week has been shown to work for most people (results take at least eight weeks to be noticeable). But exercise research in HIV remains in its infancy. Sticking to an exercise program can be a challenge for many people who lead busy lives or can't afford to join a gym. But effective home exercise programs are available and could be part of the health counseling given by health care providers and organizations.

Liposuction, assisted by ultrasound, seems to be effective at removing fat from the hump that can occur at the back of the neck. Breaking the fat fibers with ultrasound can loosen them up for easier removal. But this can not be used for removing the visceral fat that surrounds organs in the belly, since removing that is too risky. Some insurance plans and Medicare pay for liposuction when the fat gain is associated with pain or sleep disorders.

Fat gain can also occur in the upper part of the body, especially in the breasts. Some studies show increases in estradiol, a female hormone, in men taking Sustiva. This may cause gynecomastia (increased breast size) in a few people. Drugs like Arimidex, an estrogen blocker, or switching from Sustiva can help those who are in early stages of this problem.

Fat burners are being promoted by some TV commercials. But they have not been shown to work and can increase blood pressure and anxiety. Also, beware of nutritional growth hormone supplements -- there are no data indicating that they work.

Measuring Progress

Current Trials

A few studies are currently enrolling in the U.S. to find the best ways to improve cholesterol, triglycerides, and body composition in people with HIV. More info on these studies can be found online by looking for the words in bold under "Choose a treatment" at trialsearch.org.

A trial in Houston combines exercise with Niacin (a vitamin that may raise good cholesterol), Tricor (used to lower triglycerides), and prepared meals to look for improvements in lipids and visceral fat.

A Boston trial is studying Avandia plus leptin.

Another in St. Louis will look at Actos with exercise for improving insulin resistance, heart metabolism, and heart function.

One in Dallas will compare four approaches:

a high carbohydrate vs. a high cis-monounsaturated fatty acid diet

aerobic exercise with dietary advice

omega-3 fish oil capsules

leptin

The interventions are aimed at improving elevated lipids, insulin resistance, and diabetes.

A Los Angeles trial is studying whether switching women from a protease inhibitor or a non-nucleoside like Sustiva to Isentress will reduce body fat in six months.

Another at ACRIA and other sites in New York City is looking at Serostim (human growth hormone) with or without Avandia to study the effects on visceral fat.

Finally, a study in Los Angeles is combining L-carnitine, a nutritional supplement, with exercise to see if it improves muscle function.

We know when our bodies are changing by the way our clothes fit. Some people go one step further and measure their body dimensions before starting any new program or treatment.

The full-body DEXA scan is the gold standard test in lipodystrophy research, but is hardly used in clinical practice and cannot differentiate between visceral and subcutaneous fat. It's very useful since it gives information about fat, muscle mass, and bone density in every part of the body. It's not expensive (around $130) and is usually covered by Medicare and insurance. It should measure the full body and not just the hip area. Low bone density has also been linked to HIV, so this scan can be useful in detecting early bone changes before fractures happen, but this may not be covered by some insurance plans. A DEXA scan could be considered when someone first tests HIV-positive and then every few years to assess body changes and justify reimbursement for needed treatments. However, there are currently no guidelines for its use in the care of people with HIV.

The best way to assess visceral fat loss is the use of CT scans of the area around the belly button (at the level of vertebrae L4-L5). However, this method is used mostly in research since most insurance companies will not pay for it.

Between 30% and 50% of people with visceral fat may have impaired glucose tolerance (their bodies do not use sugars for energy very well) and may be pre-diabetic. A glucose tolerance test can reveal that problem. Glucose intolerance has been linked to fat gain, increased triglycerides, and development of diabetes. An improvement in glucose tolerance usually leads to fat loss and better lipids.

Conclusion

There is still much to be learned about visceral fat gains and HIV. The first FDA-approved treatment may be available soon, but may come with the barriers of high cost and limited access. There remains a great need for more nutrition and exercise counseling, building on studies of non-pharmaceutical options that cost little to nothing. As people with HIV grow older, advocacy is needed to push for studies of the effect of HIV and its treatment on the body, and to urge insurance companies to reimburse all treatment approaches. Lipodystrophy is a clinical problem that affects quality of life and possibly long-term survival, and it should not be regarded as purely a cosmetic concern.

Nelson Vergel is a treatment activist and the Director of Program For Wellness Restoration: powerusa.org.

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